The goal of this project is to develop new imaging probes that exploit the rapidly advancing field of nanotechnology. We will focus on developing contrast agents for early staging of cancer that will be 10 to 100 times more sensitive than currently available while simultaneously reporting on the physiological properties of lesions and tumors. This will be accomplished by synthesizing entirely new classes of multimodal (optical/MR) bioactivated-probes attached to nanoparticles for imaging in vivo cell fate and migration, gene expression and secondary messenger activation. Multimodal agents take advantage of the sensitivity of detection of one technique combined with the high spatial resolution of a second imaging modality. The principle barriers to the development of new classes of contrast agents for noninvasive imaging of cancer can be summarized by three fundamental problems: i. amplification of the signal;ii. in vivo delivery; and iii. development of biochemical reporters. Recent advances in nanotechnology have demonstrated that the solutions to these problems may be at hand. By coupling the unique properties of nanomaterials that function as a platform-diagnostic (T1 + optical + T2) with new types of biochemically activated probes, entirely new generations of contrast agents can be developed that are capable of detecting cancer at cellular level in whole organisms. It is clear that molecular imaging is becoming an important tool in the biological sciences and the clinical arena. In order to maximize the impact of these techniques, functional and far more sensitive contrast agents must be investigated and developed. Our entire approach is designed to "close the- loop:" i.e., design to synthesis and characterization, to in vivo delivery, to biological validation and imaging. We have identified 5 specfic aims for the syntheis and evaluation of nanoparticle and bioactivated contrast agents that focus on D-glucoronidase, caspases, MMPs and cathepsins.